Rheumatoid arthritis (RA) is an autoimmune arthropathy associated with systemic inflammatory manifestations. In RA, the synovium, the inner lining of synovial joints, is abnormal. There is infiltration of acute inflammatory cells in the synovium, which undergoes hypertrophy, resulting in effusion of the joint. Hyperplastic synovium may also lead to erosion of the adjacent cartilage and bone, causing joint destruction. The end result is joint inflammation, effusion, joint and adjacent ligament destruction, joint deformity and, finally, loss of function. RA is the most common inflammatory joint disease, affecting virtually all populations in the world. It is a serious worldwide health problem.
Traditional treatment of RA centers on the use of anti-inflammatory drugs to suppress joint inflammation and production of cytokines. Immunomodulatory drugs may also be effective, including immunosuppressive drugs such as corticosteroids, methotrexate and cyclosporine (Tamer, et al., Nat. Clin. Pract. Rheumatol., 3:336-45 (2007)). Other disease modifying medications including penicillamine and gold may also be used.
The pathogenesis of RA is complex and has not been fully defined. However, a number of cytokines, including interleukin (IL)-6, IL-15, IL-17, and tumor necrosis factor, have been implicated in causing joint and systemic inflammation (Tamer, et al., Nat. Clin. Pract. Rheumatol., 3:336-45 (2007)). The cytokine signaling pathways incriminated in RA pathogenesis include the tumor necrosis factor alpha (TNF-α) pathway, the mitogen activated protein kinase (MAPK) pathway, the Janus kinases (JAK) pathway, and the signal transducer and activator of transcription (STAT) pathways. An important molecule downstream of TNF-α pathway is the transcription factor nuclear factor kappa B (NFκB). These pathways play important parts in the synovial proliferation, and the consequent joint damage characteristic of RA (Tamer, et al., Nat. Clin. Pract. Rheumatol., 3:336-45 (2007)).
Recently, it has also been shown that the synovium plays an active role in joint inflammation. Fibroblast-like synoviocytes are the most important cellular component of the synovium. Synoviocytes are necessary for the initiation and propagation of the inflammation observed in RA, mediating both cartilage damage and acute and chronic inflammation (Lipsky, N. Engl. J. Med., 356:2419-20 (2007)). The importance of the synoviocytes is further shown by the finding that mouse models deficient in a functional synovium are resistant to experimental arthritis (Amano, et al., Genes Dev., 17:2436-49 (2003); Lee, et al., Science, 315:1006-10 (2007)).
Targeting of two of the key pathways involved putatively in RA pathogenesis has shown that this may be a potential therapeutic strategy (Choy, et al., N. Engl. J. Med., 344:907-16 (2001)). Treatment with infliximab, a chimeric monoclonal antibody against TNF-α, results in significant improvement in joint inflammation and halts the progression of joint damage (Lisky, et al., N. Engl. J. Med., 343:1594-602 (2000)). Treatment with tocilizumab, an antibody against the IL-6 receptor (IL-6R), leads to significant control of symptoms in RA patients (Smolen, et al., Lancet, 371:987-97 (2008)).
The use of infliximab, however, has been associated with tuberculosis (Keane, et al., N. Engl. J. Med., 345:1098-104 (2001)), and other opportunistic infections including pneumocystis pneumonia (Harigai, et al., N. Engl. J. Med., 357:1874-6 (2007))) and cerebral toxoplasmosis (Young, et al., N. Engl. J. Med., 353:1530-1 (2005)). Serious infections have also happened to patients on tocilizumab treatment (Nishimoto, et al., Ann. Rheum Dis., (2008)). These medications are also expensive. Moreover, because they are given intravenously, they are expensive and cumbersome for the patient.
Therefore, it is an object of the invention to provide formulations and methods for suppressing the growth and activity of synoviocytes in rheumatoid arthritis. Because synoviocytes may also play important pathogenetic roles in other inflammatory arthritis, it is another object of the invention to provide formulations and methods for suppressing the growth and activity of synoviocytes in other inflammatory arthritis.
It is yet another object of the invention to provide formulations and methods for treating inflammatory arthritis.